A number of compounds of industrial interest, in particular pharmaceuticals for human or veterinary use, contain a sulfinyl or sulfonyl group. Their synthesis usually comprises an oxidation step wherein a thioether intermediate (—S—) is transformed into a sulfinyl (—SO—) or sulfonyl (—SO2—) compound. Different oxidizing agents are available for this oxidation, such as those described by S. Uemura in “Comprehensive Organic Synthesis”, chapter 6.2, edited B. M. Trost and J. Fleming, Pergamon Press (1991). Nevertheless, only some of these oxidizing agents are suitable for industrial application, due to the fact that they are not easily available on the market, to environment-safety and hygiene problems related to their use, or to their poor chemical selectivity. Among those suitable for industrial use, hydrogen peroxide and sodium hypochlorite are usually preferred, as they are commercially available in large amounts and at low cost. However, it is known that the use of hydrogen peroxide on an industrial scale is hazardous, as reported in “Handbook of Chemical Hazards”, E. Brewtherick and Butterworths (1979). Moreover, the oxidation of organic compounds with hydrogen peroxide is very often carried out in the presence of catalysts based on transition metals, such as tungstenum, titanium, vanadium and molybdenum. The removal of these catalysts from the reaction product is recognizedly troublesome, as it requires additional purification steps with consequent increase in production costs and decrease in yield.
In general, the oxidizing power of sodium hypochlorite is not sufficient to obtain sulfonyl derivatives. Moreover, in most cases the oxidation of thioethers with sodium hypochlorite is not sufficiently selective and leads to undesired by-products.
A known medicament that contains a sulfinyl group is modafinil, i.e. 2-[(diphenylmethyl)sulfinyl]acetamide. According to various synthetic methods, intermediate 2-[(diphenylmethyl)thio]acetic acid or 2-[(diphenylmethyl)thio]acetamide is oxidized with hydrogen peroxide to give 2-[(diphenylmethyl)sulfinyl]acetic acid, or 2-[(diphenylmethyl)sulfinyl]acetamide, respectively. This oxidation, usually performed with 110 volumes hydrogen peroxide, involves safety problems. Similar problems also occur in the synthesis of other biologically active sulfinyl compounds, such as sulindac, i.e. (Z)-5-fluoro-2-methyl-1-[[4-(methyl-sulfinyl)phenyl]methylene]-1H-indene-3-acetic acid, and the so-called “prazoles”, i.e. [[(pyridyl)methyl]sulfinyl]benzimidazole derivatives, which are known anti-secretory agents.
There is therefore still the need of a further cheap oxidizing agent that allows to operate safely and to easily control the reaction, so as avoid formation of by-products, such as N-oxides and/or sulfonyl derivatives, also satisfies the requirements of regulatory authorities. These requirements are particularly strict for pharmaceutical products, wherein the said by-products should be present in the lowest amount.
It has now been found that the oxidation of a thioether group to a sulfinyl (sulfoxide) or sulfonyl (sulfone) group can be advantageously carried out using ε-phthalimidoperhexanoic acid as the oxidizing agent. In particular, it has been found that ε-phthalimidoperhexanoic acid can be easily and safely handled and used on an industrial scale without the need of particular plants or specific safety procedures. Moreover, ε-phthalimidoperhexanoic acid and its reduced by-product, ε-phthalimidohexanoic acid, are substantially low polluting and can be advantageously used on a large scale.
ε-Phthalimidoperhexanoic acid is a stable, commercially available, solid and cheap product, used for the preparation of cosmetic formulations and detergents for domestic or industrial use.